Zhu Li-Hua, Huang Ling, Zhang Xiaojing, Zhang Peng, Zhang Shu-Min, Guan Hongjing, Zhang Yan, Zhu Xue-Yong, Tian Song, Deng Keqiong, Li Hongliang
*Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
‡State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Clin Sci (Lond). 2015 Jul;129(2):129-45. doi: 10.1042/CS20140679.
Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases [Zhu et al. (2014) J. Hepatol. 60, 1046-1054; Bian et al. (2012) J. Mol. Med. 90, 895-910; Wang et al. (2013) Exp. Neurol. 247, 506-516; Yan et al. (2011) Cardiovasc. Res. 92, 85-94]. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expression was significantly down-regulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wire injury-stimulated vascular tissue. Using a gain-of-function approach, overexpression of mindin in VSMCs exhibited strong anti-proliferative and anti-migratory effects on VSMCs, whereas significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in smooth muscle cells (SMCs). These mice exhibited blunted VSMC proliferation, migration and phenotypic switching. Conversely, deletion of mindin dramatically exacerbated neointima formation in a wire-injury mouse model, which was further confirmed in a balloon injury-induced vascular lesion model using a novel mindin-KO (knockout) rat strain. From a mechanistic standpoint, the AKT (Protein Kinase B)-GSK3β (glycogen synthase kinase 3β)/mTOR (mammalian target of rapamycin)-FOXO3A (forkhead box O)-FOXO1 signalling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated hyperplasia, suggesting that mindin-mediated neointima formation is AKT-dependent. Taken together, our findings demonstrate that mindin protects against vascular hyperplasia by suppression of abnormal VSMC proliferation, migration and phenotypic switching in an AKT-dependent manner. Up-regulation of mindin might represent an effective therapy for vascular-remodelling-related diseases.
Mindin/血小板反应蛋白2（spondin 2）是一种细胞外基质（ECM）成分，属于血小板反应蛋白1型（TSR）分子类别，在炎症反应、血管生成和代谢紊乱的调节中发挥着重要作用。我们最近的研究表明，mindin在很大程度上参与了心血管和脑血管疾病的发生和发展[朱等人（2014年），《肝脏病学杂志》60卷，第1046 - 1054页；边等人（2012年），《分子医学杂志》90卷，第895 - 910页；王等人（2013年），《实验神经病学》247卷，第506 - 516页；严等人（2011年），《心血管研究》92卷，第85 - 94页]。然而，mindin在新生内膜形成中的调节功能仍不清楚。在本研究中，在血小板衍生生长因子 - BB（PDGF - BB）刺激的血管平滑肌细胞（VSMC）和丝线损伤刺激的血管组织中，mindin表达显著下调。采用功能获得方法，VSMC中mindin的过表达对VSMC表现出强烈的抗增殖和抗迁移作用，而在平滑肌细胞（SMC）中特异性表达mindin的转基因（TG）小鼠中观察到内膜增生明显受到抑制。这些小鼠的VSMC增殖、迁移和表型转换减弱。相反，在丝线损伤小鼠模型中，mindin的缺失显著加剧了新生内膜形成，这在使用新型mindin基因敲除（KO）大鼠品系的球囊损伤诱导血管病变模型中得到进一步证实。从机制角度来看，AKT（蛋白激酶B） - GSK3β（糖原合酶激酶3β）/mTOR（雷帕霉素哺乳动物靶标） - FOXO3A（叉头框O） - FOXO1信号轴负责在内膜增厚过程中对mindin的调节。有趣的是，一种AKT抑制剂在很大程度上逆转了mindin基因敲除诱导的增生加重，表明mindin介导的新生内膜形成是AKT依赖性的。综上所述，我们的研究结果表明，mindin通过以AKT依赖性方式抑制异常的VSMC增殖、迁移和表型转换来防止血管增生。mindin的上调可能是治疗血管重塑相关疾病的有效疗法。
